Efficacy and safety of larotrectinib in pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive cancer: An expanded dataset.
Authors: Leo Mascarenhas, Cornelis Martinus van Tilburg, Francois Doz, C. Michel Zwaan, Catherine M. Albert, Claudia Blattman, Birgit Geoerger, Steven G. DuBois, Noah Federman, Ramamoorthy Nagasubramanian, Alberto S. Pappo, Tanya Carens Watt, Ricarda Norenberg, Marc Mardoche Fellous, Esther A. De La Cuesta, Theodore Willis Laetsch, Rui-hua Xu
Journal: Journal of Clinical Oncology (2022)

10030 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types across all ages. Larotrectinib is a first-in-class, central nervous system (CNS)-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for pediatric and adult patients (pts) with TRK fusion-positive cancer, demonstrating an objective response rate (ORR) of 88% across 78 pediatric pts with non-CNS cancers (van Tilburg et al, SIOP 2021). We report an analysis of the efficacy and safety of larotrectinib in an expanded dataset of pediatric pts with TRK fusion-positive cancer. Methods: Pediatric pts (&lt; 18 years) with non-CNS TRK fusion-positive cancer in larotrectinib clinical trials (NCT02637687, NCT02576431) were included and ORR (RECIST v1.1) was investigator (INV)-assessed. Data cut-off was July 20, 2021. Results: A total of 94 pts were included in this analysis. Tumor types included infantile fibrosarcoma (52%), other soft tissue sarcoma (40%), congenital mesoblastic nephroma (2%), thyroid cancer (2%), bone sarcoma (1%), breast cancer (1%), and melanoma (1%). Pts had gene fusions involving NTRK1 (43%), NTRK2 (3%), or NTRK3 (54%). Median age was 2.2 years (range 0–18 years). Of the 62 (66%) pts who received prior systemic therapy, 32 (52%) received ≥2 lines. The INV-assessed best ORR for the 93 evaluable pts was 84% (95% confidence interval [CI] 75–91): 35 (38%) complete response (CR; including two pending confirmation and 10 pathological CR), 43 (46%) partial response (two pending confirmation), 11 (12%) stable disease, two (2%) progressive disease, and two (2%) not determined. The median time to response was 1.8 months. Overall, median duration of response was 43.3 months (95% CI 23.4–NE); median follow-up was 26.0 months. Median progression-free survival and overall survival (OS) were 37.4 months (95% CI 22–NE) and not reached, respectively; median follow-up was 21.2 and 30.3 months, respectively. The 36-month OS rate was 93% (95% CI 86–99). Treatment duration ranged from 1+ to 63+ months. At data cut-off, 31 pts had progressed; 18 continued treatment post-progression for ≥4 weeks. There were no treatment-related deaths. Treatment-related adverse events (TRAEs) occurred in 81% of pts (23% were Grade [G] 1, 28% G2, 25% G3, and 5% G4). The most common TRAE was increased aspartate aminotransferase (31 pts [33%]). Four pts (4%) discontinued treatment due to TRAEs. Neurological TRAEs occurred in 12% of pts (5% were G1, 4% G2, and 2% G3). The most common neurological TRAE was headache (5 pts [5%]). Conclusions: In this expanded dataset, larotrectinib continues to demonstrate rapid and durable tumor-agnostic efficacy, extended survival, and a favorable safety profile in pediatric pts with TRK fusion-positive cancer. These results highlight the importance of identifying NTRK gene fusions in pediatric solid tumors. Clinical trial information: NCT02576431, NCT02637687.